A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer

Abstract

BackgroundThere is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC).MethodsThis Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals.ResultsThirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4.ConclusionProduction of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

“…Therefore, gaining a better understanding of the heterogeneity and molecular composition of EVs could allow us to determine more suitable subpopulations for certain EV-based therapeutics (i.e., by identifying subpopulations that can exert particular effects without unwanted side-effects). The vesicle doses have varied across the existing studies, ranging from 1 to 500 μg per in vivo injection [12,104,105,149–151], further emphasizing that the heterogeneity of EVs needs to be characterized to avoid the induction of adverse effects in patients. Although some methods have been developed to detect EV heterogeneity, their detection sensitivities and specificities must be improved to enable researchers to precisely characterize each subpopulation and the compositions of individual vesicles.…”

Scalable, cGMP‐compatible purification of extracellular vesicles carrying bioactive human heterodimeric IL‐15/lactadherin complexes

“…Immunomodulation using natural or engineered EV, especially for the treatment of cancer, is being explored by multiple groups [5]. Notably, several clinical trials have tested primary human dendritic cell-derived EV as a cell-free cancer vaccine platform [6,7]. One of the immunostimulatory effects associated with dendritic cell EV was direct activation of NK cells through NKG2D and interleukin-15 (IL-15) pathways [8].…”

The exosomes in tumor immunity

“…Vaccination of patients with DEXs from metastatic melanoma and advanced non-small cell lung cancer resulted in activation of immune responses and prolonged stability of diseases, as demonstrated in phase I clinical trials. 77,78 However, how to break down the obstacles of host immunosuppression and rescue insufficient T cell responses when using DEXs as tumor vaccines calls for further studies.…”